The relevance of tumor genotype, as with CAF and ECM production, and sustenance of an immunosuppressive microenvironment induced via tumor cells derived-EVs was also investigated with a specific focus on SMAD4 loss, associated with worse prognosis and increased cell proliferation and metastases, a unique characteristic of gastrointestinal cancers and representative of upwards of 50% of PDA profiles. Here, SMAD4 is linked to neoplasm.