Research

Despite innovations in combination chemotherapy, targeted therapies, and immunotherapies, most advanced cancers remain incurable. Deciphering the mechanisms that govern the initiation, progression, and maintenance of cancer will facilitate the development of novel strategies for prevention and therapy.

For cancers to arise, cells must acquire the capacity for sustained proliferation while overcoming both intrinsic evolutionary constraints and constraints imposed by the host environment. These properties may be attained through the sequential acquisition of genetic mutations in proto-oncogenes and tumor suppressor genes. Comprehensive genome sequencing efforts have catalogued human cancer mutations, enabling the use of therapies that target these mutated oncoproteins. Nonetheless, cancers frequently evade target inhibition. We demonstrated, for example, that pancreatic cancer cells tolerate genetic ablation of their initiating oncogene KRAS through rewiring of signal transduction. Similar adaptive mechanisms (signaling-based, transcriptional, epigenetic, and metabolic) play a critical role in the maintenance of advanced cancers in the absence of new mutations. In contrast, how non-mutational adaptations impact the earlier stages of tumorigenesis remains poorly understood.

Using genetically-engineered mouse models that closely recapitulate human lung and pancreatic cancers, we have shown that gene mutations are permissive, but insufficient, to drive clonal cancer evolution, consistent with the need for additional cellular adaptations. Furthermore, we have demonstrated that host adaptations to environmental stresses, such as diet and obesity, may facilitate tumor progression in the absence of new mutations. Our research focuses on elucidating the molecular basis of these tumor cell and host adaptations in hopes of defining new approaches for the prevention and treatment of these recalcitrant cancers.

Targeting KRAS in pancreatic cancer

Oncogenic mutations in the proto-oncogene KRAS occur in >90% of pancreatic ductal adenocarcinoma (PDAC) and drive tumor initiation and maintenance. KRAS is a small GTPase that acts as a molecular switch to regulate proliferation, differentiation, metabolism, and survival. Oncogenic point mutations in KRAS result in constitutive activation of the mitogen-activated protein kinase (MAPK), PI3K, and other downstream signaling pathways. Leveraging isogenic KRAS-intact and deficient cells, functional genomics/proximity proteomics/pharmacologic screens, and state-of-the-art RAS inhibitors, we aim to understand mechanisms governing KRAS signaling in PDAC and response and resistance to KRAS inhibition.

Determining mechanisms of resistance to KRAS inhibition

Recent advances have led to the development of allele-specific and multi-RAS(ON) inhibitors for clinical use. While preclinical and clinical data confirm that targeting KRAS can suppress tumor growth, adaptive resistance emerges rapidly. Resistance mechanisms include genetic reactivation of RTK/RAS, MAPK, or PI3K signaling; however, many cases lack identifiable genetic drivers, highlighting critical non-genetic adaptive pathways. We are studying the mechanistic basis by which PI3K regulates RAS signaling to confer resistance to KRAS inhibition, membrane proximal signaling interactions that mediate RAS signaling, and how protein degradation complexes mediate resistance to KRAS inhibition.

Defining how distinct KRAS alleles impact the cellular signaling state of PDAC cells

Distinct KRAS alleles have been reported to have biochemical and signaling differences, underscoring the need to understand allele-specific KRAS biology. Using unbiased transcriptomic, proteomic, and phosphoproteomic approaches in isogenic KRAS-expressing PDAC cells lines, we have defined shared and divergent impacts of diverse KRAS mutations on cell signaling.

Team Members

Current:

Cassie Markham, BS (PhD candidate)
Yanixa Quinones-Aviles, BS (PhD candidate)

Xiangyu (Gigi) Ge, PhD (Graduate student, 2020-2025)
Jaffarguriqbal Singh, DO (Postgraduate associate, 2017-2019)

Collaborators:

Moitrayee Bhattacharyya, PhD
Kallol Gupta, PhD
Yansheng Liu, PhD

Deciphering the mechanistic link between obesity and pancreatic cancer

Epidemiologic studies in human cohorts have confirmed an association between obesity and an increased risk of developing over a dozen types of cancer, including pancreatic cancer. Yet, the precise mechanisms by which obesity drives tumor progression remain elusive and represent a major untapped target to develop novel strategies for cancer prevention and therapy.

Hormone Dysregulation

Genetically-engineered mouse models (GEMMs) that faithfully recapitulate the genetics and morphology of human tumors are an underutilized tool to understand how modifiable risk factors influence tumor development. We developed a novel GEMM of obesity-associated pancreatic cancer demonstrating a causal and reversible role for obesity in early pancreatic cancer development, wherein obesity accelerates tumor progression while weight loss impedes it. Leveraging this model, we identified a previously unappreciated endocrine-exocrine signaling axis, distinct from insulin, which drives pancreatic tumorigenesis. By combining single-cell RNA-sequencing and conditional knockout models, we discovered that obesity drives stress-induced endocrine islet β cell expression of the peptide hormone cholecystokinin (CCK) that drives exocrine acinar cell state alterations and peri-islet tumor formation. We are actively studying how islet CCK may serve as both a biomarker or risk and target for therapy, how islet CCK promotes tumorigenesis and how pharmacologic modulation of β cell stress impacts carcinogenesis.

Mechanisms of high-fat diet-associated pancreatic carcinogenesis

Obesity is frequently accompanied by increased consumption of high-fat diets, yet the mechanisms by which dietary fat – and specifically fat composition – impacts pancreatic cancer progression remain unclear. Using GEMMs and quantitative lipidomic approaches, we study how different, frequently consumed, dietary fatty acids remodel tumor cell membranes and reshape the metabolic environment to influence pancreatic tumor initiation and progression. By uncovering how specific dietary fats reprogram tumor metabolism, we aim to identify metabolic vulnerabilities that could guide precision nutrition strategies and therapeutic approaches to reduce pancreatic cancer risk.

Impact of obesity-related gut microbiome on pancreatic carcinogenesis

Obesity is associated with profound changes in the gut microbiome that influence host metabolism, inflammation, and immune signaling. However, whether these changes in microbial communities directly contribute to pancreatic tumorigenesis remains poorly understood. We investigate how obesity-associated microbial communities shape pancreatic cancer development using longitudinal microbiome profiling, cohousing experiments, and fecal microbiota transplantation in mouse models. These studies aim to identify microbial taxa and metabolic pathways that correlate with obesity and disease progression. Ultimately, this work seeks to determine whether microbiome-derived signals act as intermediaries linking obesity to pancreatic cancer, potentially revealing new strategies to modify cancer risk through microbial or metabolic interventions.

Effect of obesity-associated feeding behaviors on PDAC initiation

Obesity is associated with extremes in feeding, such as overeating and/or binging, which may be distinct from overall food intake and could be sufficient to induce repeated stress and/or injury in the exocrine pancreas. Using unique feeding regimens under the control of automated feeders, we are exploring the impact of extreme changes in feeding patterns in the promotion of acinar and/or islet reprogramming to induce the initiation of pancreatic cancer.

Team Members

Current:

Shravani Daptardar, MS (Postgraduate associate)
Jeremy Jacox, MD, PhD (Instructor/Medical oncologist, former Post-doctoral fellow)
Meera Kharwa, MS (Postgraduate associate)
Daniel McQuaid, BS (MD/PhD candidate)
Christian F. Ruiz, PhD (Associate research scientist)
Christy Zheng, BS (PhD candidate)

Cathy Garcia, PhD (graduate student, 2019-2024)
Lauren Lawres, MS (Research associate, 2018-2022)
Rylee McDonnell (Postgraduate associate, 2021-2022)
Jaffarguriqbal Singh, DO (Postgraduate associate, 2017-2019)
Chaitanya Vattem, MS (Postgraduate associate, 2023-2025)

Collaborators:

Fred Gorelick, MD, PhD
Ania Jastreboff, MD, PhD
Richard Kibbey, MD, PhD
Smita Krishnaswamy, PhD
Ken Huaijin Loh, PhD
Noah Palm, PhD
Matthew Rodeheffer, PhD
John Wysolmerski, MD

Tracing tumor progression in KRAS-driven cancers

Although it has become increasingly clear that cancers display significant cellular heterogeneity, the spatial growth dynamics of genetically distinct clones within developing solid tumors remain poorly understood. Leveraging the mosaic analysis with double markers (MADM) system, we have traced subclonal populations retaining or lacking p53 within oncogenic KRAS-initiated lung and pancreatic tumors. In both tumor types, p53 loss is permissive but not sufficient for progression to advanced adenocarcinoma. By applying single-cell molecular analyses of isolated cells and intact tissues, we hope to uncover novel drivers of tumor progression, which may represent targets for cancer interception

Epigenetic and metabolic determinants of cancer evolution

Leveraging chromatin tracing to map the evolution of 3D genomic architectures in intact tissues at single-cell genome-wide resolution, we identified stereotypical, non-monotic changes in chromatin conformations during lung and pancreatic cancer evolution. Furthermore, by combining single-cell 3D genomic and transcriptomic profiling, we identified candidate cancer progression drivers – regulated at the level of the 3D genome – that delineate prognosis and potential vulnerabilities, which we are validating using in vitro and in vivo models. In parallel, we are analyzing the evolution of the metabolome and lipidome as lung cancers progress using in situ mass spectrometry-based methods (MALDI).

Mechanisms of allele-specific tumor suppression by p53

p53 is the most frequently mutated tumor suppressor protein across cancers with point and truncation mutations occurring in more than half of lung and pancreatic cancers. Yet, how p53 suppresses tumorigenesis in vivo remains incompletely understood. Furthermore, whether and how diverse p53 point mutations differentially impact tumor progression is not well-defined. By integrating varied p53 point and null mutation alleles into MADM for in vivo comparative analysis, we are studying stage-specific differences in tumor suppression of these alleles in pancreatic cancer and the underlying mechanisms that lead to these phenotypic effects.

Team Members

Current:

Sherry Agabiti, PhD (Associate research scientist)
Ilze Olivi Gomes, MS (PhD candidate)

Andrew Tang, BS (Yale undergraduate, 2021-2024)

Collaborators:

Yansheng Liu, PhD
Jeffrey Townsend, PhD
Siyuan Wang, PhD

Deciphering the effects of host-environment interactions on anti-tumor immunity in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a profoundly dense stroma, immune suppression, and limited response to immunotherapy. While much work has focused on tumor-intrinsic mechanisms of immune evasion, less is understood about how host factors — such as obesity — shape anti-tumor immunity. Together with the Joshi laboratory at Yale, we have developed a novel neoantigen-bearing model of pancreatic cancer, NINJA PDAC, affording inducible neoantigens after formation of the tumor microenvironment (TME). Using this platform and other engineered organoid models of PDAC,we are actively studying how obesity modulates tumor-immune interactions in the native TME.

Effect of obesity on anti-tumor immunity

Our research examines how obesity influences antigen-specific adaptive immune responses in PDAC. Using engineered murine organoid models that express defined B cell, CD4⁺, and CD8⁺ T cell antigens, we study how immune coordination against tumor growth differs between lean and obese hosts. By integrating tumor biology with alterations in systemic metabolism, we aim to clarify how host physiology influences cancer progression and response to immunotherapy.

Mechanisms mediating immune-exclusion

We found stromal immune exclusion is the rate-limiting mechanism of immunosuppression in the NINJA PDAC model, affording an opportunity to probe known (e.g., CXCR4-CXCL12 axis) and unknown mechanisms within the TME that lead to stroma-mediated exclusion.

Impact of novel immune therapeutic combinations

Surmounting immune barriers in metastatic PDAC requires combinations impacting tumor cytotoxicity, stromal-mediated immunosuppression, and neoantigen- directed T-cell responses. We are leveraging our unique preclinical models to combine targeted inhibitors (e.g., KRAS-inhibition) and immunotherapies and determine mechanisms of response and resistance.

Team Members

Current:

Shravani Daptardar, MS (Post-graduate associate)
Jeremy B. Jacox, MD, PhD (Instructor/Medical oncologist, former Post-doctoral fellow)
Melanie Ovalle (Yale undergraduate)
Akin Sogunro, BS (MD/PhD candidate)

Dhruvi Shah, MS (Post-graduate associate, 2021-2023)
Chaitanya Vattem, MS (Post-graduate associate, 2023-2025)

Collaborators:

Nikhil Joshi, PhD