Targeting tumour-promoting malignant cell-fibroblast crosstalk in pancreatic cancer
Lead Research Organisation:
University of Cambridge
Abstract
Context and Challenge
Pancreatic cancer (PDAC) is lethal for most patients, with fewer than 10% surviving more than 5 years. This is largely because the disease is diagnosed late, when it has spread to other organs, a process known as ‘metastasis’. For metastatic patients, treatments are ineffective. Additionally, PDAC is characterised by poorly understood features that promote disease progression and therapy resistance, including non-cancerous cells known as cancer-associated ‘fibroblasts’ (CAFs) that constitute most of the tumour. Our Lab’s goal is to understand how cancer cells and CAFs cooperate to drive PDAC progression, and to apply this knowledge to group patients and develop tailored therapeutics. I previously discovered that CAFs exist in two major states: myofibroblastic (myCAFs) and inflammatory (iCAFs). Over the past three years, my laboratory extended this work, systematically studying processes operating in CAFs and cancer cells, and the crosstalk between these populations. In this manner, we identified new PDAC vulnerabilities, including promotion of metastasis by a subset of myCAFs, and cancer cells’ DNA alterations-dependent signalling that shape CAF composition. These findings are beginning to unravel the complex processes that govern cancer cell-fibroblast signalling in one of the deadliest and enigmatic cancers. However, our knowledge remains largely limited to primary pancreatic tumours rather than metastases, which are the main cause of patients’ death. Therefore, we will build from our work to understand the functional heterogeneity of fibroblasts in metastatic PDAC. This knowledge is required if we are to develop better ways of diagnosing PDAC earlier and treating it more effectively.
Objectives and Aims
Our knowledge of PDAC biology is largely limited to tumours with two DNA alterations known as Kras-G12D and mutant-p53. However, my work has highlighted how additional alterations shape CAF composition, PDAC progression and therapy response. I will build from this work to understand how distinct DNA alterations impact malignant cell-intrinsic and -extrinsic drivers of PDAC metastasis with the goal to develop therapeutics for groups of patients. To this end, I will combine patient-relevant organoid-derived models with innovative mouse models for depletion of specific fibroblast populations. We will focus on metastases in the liver and lungs, which are most prevalent in patients, and PDACs with combinations of four DNA alterations common in patients: Kras-G12D, mutant-p53, Smad4-loss and Cdkn2a-loss.
Objective 1: Identifying tumour-promoting cancer cell-fibroblast interactions in metastatic PDAC. We will analyse matched primary tumours and metastases from organoid-derived mouse models to identify cancer cell-fibroblast drivers of PDAC progression. Candidate targets will be prioritised according to strict criteria, including validation by orthogonal approaches (WP1-WP2), human biology (WP3) and availability of pharmacological inhibitors.
Objective 2: Targeting tumour-promoting cancer cell-fibroblast interactions in metastatic PDAC. We found that iCAFs are enriched in Smad4-deleted PDAC. We will thus target cancer cell-iCAF crosstalk leveraging mouse models for iCAF depletion (WP4). This work, together with Objective 1, will guide the design of pharmacological strategies to target tumour/metastasis-promoting cancer cell-fibroblast crosstalk in PDAC (WP5).
Applications and Benefits
My work will identify biological processes underpinning metastasis and pinpoint new treatment targets for PDAC. Our models and datasets will be made available directly to the global research community, ensuring that they are widely accessible and deployed. As similarities across malignancies exist in terms of fibroblast functions, and metastasis is the primary cause of death of cancer patients, my work could benefit the broader scientific and clinical community.
Pancreatic cancer (PDAC) is lethal for most patients, with fewer than 10% surviving more than 5 years. This is largely because the disease is diagnosed late, when it has spread to other organs, a process known as ‘metastasis’. For metastatic patients, treatments are ineffective. Additionally, PDAC is characterised by poorly understood features that promote disease progression and therapy resistance, including non-cancerous cells known as cancer-associated ‘fibroblasts’ (CAFs) that constitute most of the tumour. Our Lab’s goal is to understand how cancer cells and CAFs cooperate to drive PDAC progression, and to apply this knowledge to group patients and develop tailored therapeutics. I previously discovered that CAFs exist in two major states: myofibroblastic (myCAFs) and inflammatory (iCAFs). Over the past three years, my laboratory extended this work, systematically studying processes operating in CAFs and cancer cells, and the crosstalk between these populations. In this manner, we identified new PDAC vulnerabilities, including promotion of metastasis by a subset of myCAFs, and cancer cells’ DNA alterations-dependent signalling that shape CAF composition. These findings are beginning to unravel the complex processes that govern cancer cell-fibroblast signalling in one of the deadliest and enigmatic cancers. However, our knowledge remains largely limited to primary pancreatic tumours rather than metastases, which are the main cause of patients’ death. Therefore, we will build from our work to understand the functional heterogeneity of fibroblasts in metastatic PDAC. This knowledge is required if we are to develop better ways of diagnosing PDAC earlier and treating it more effectively.
Objectives and Aims
Our knowledge of PDAC biology is largely limited to tumours with two DNA alterations known as Kras-G12D and mutant-p53. However, my work has highlighted how additional alterations shape CAF composition, PDAC progression and therapy response. I will build from this work to understand how distinct DNA alterations impact malignant cell-intrinsic and -extrinsic drivers of PDAC metastasis with the goal to develop therapeutics for groups of patients. To this end, I will combine patient-relevant organoid-derived models with innovative mouse models for depletion of specific fibroblast populations. We will focus on metastases in the liver and lungs, which are most prevalent in patients, and PDACs with combinations of four DNA alterations common in patients: Kras-G12D, mutant-p53, Smad4-loss and Cdkn2a-loss.
Objective 1: Identifying tumour-promoting cancer cell-fibroblast interactions in metastatic PDAC. We will analyse matched primary tumours and metastases from organoid-derived mouse models to identify cancer cell-fibroblast drivers of PDAC progression. Candidate targets will be prioritised according to strict criteria, including validation by orthogonal approaches (WP1-WP2), human biology (WP3) and availability of pharmacological inhibitors.
Objective 2: Targeting tumour-promoting cancer cell-fibroblast interactions in metastatic PDAC. We found that iCAFs are enriched in Smad4-deleted PDAC. We will thus target cancer cell-iCAF crosstalk leveraging mouse models for iCAF depletion (WP4). This work, together with Objective 1, will guide the design of pharmacological strategies to target tumour/metastasis-promoting cancer cell-fibroblast crosstalk in PDAC (WP5).
Applications and Benefits
My work will identify biological processes underpinning metastasis and pinpoint new treatment targets for PDAC. Our models and datasets will be made available directly to the global research community, ensuring that they are widely accessible and deployed. As similarities across malignancies exist in terms of fibroblast functions, and metastasis is the primary cause of death of cancer patients, my work could benefit the broader scientific and clinical community.