Characterising and targeting host dependencies of Pancreatic Ductal Adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDA) is a dismal disease with a 5-year survival rate of 12.5%. Patients with local disease are offered surgery with curative intent, chemotherapy and sometimes radiotherapy.

However, most patients (~80%) present with advanced disease and are only offered standard of care chemotherapy with limited effect.

A characteristic feature of PDA is the pathologically remodelled tumour microenvironment (TME), which creates a stiff, poorly perfused, immune suppressed, treatment recalcitrant tumour ecosystem. Therapeutic targeting of the TME has received much attention.

However, it has become increasing clear that the TME contains dichotomous tumour promoting and suppressive elements and thus detailed mechanistic understanding of the interdependencies between the malignant tumour cells and the host niche is fundamental to successfully implement TME targeting therapies.

We recently identified and characterised two lineages of pancreatic fibroblasts, defined by non-interconvertible expression of CD105, with distinct tumour permissive and restrictive functions.

We demonstrated that i) CD105neg fibroblasts suppress tumour growth in an immune-dependent manner in vivo and ii) that CD105neg fibroblasts act in a dominant manner over CD105pos fibroblasts when co-injected in vivo. Moreover, CD105pos and CD105neg fibroblasts are both present in normal healthy and tumour bearing pancreas.

Thus, given the dominant tumour restrictive effect of CD105neg fibroblasts, successful tumour development requires that malignant cells overcome this stromal restriction point.

Here I propose to study I) The mechanisms whereby CD105pos and CD105neg stromal fibroblasts regulate pancreatic cancer development and II) To determine the mechanisms whereby malignant tumour cells conscript the stromal microenvironment to bypass a tissue intrinsic stromal checkpoint and enable pancreatic cancer progression.

I will use a combination of in vivo and in vitro models of developing murine and human PDA to functionally interrogate the mechanisms whereby CD105pos and CD105neg fibroblasts control tumour development and how emerging tumour cells instructs a tumour permissive microenvironment.

I pose that understanding such mechanisms will enable us to test approaches whereby tumour restrictive effects of cancer-associated fibroblasts can be re-invigorated in fully developed tumours.