Title: STrOmal ReprograMing (STORMing) Provides New Directions to Prevent and Revert Chronic Inflammation-Associated Cancers
Funder: Cancer Research UK

Abstract: The overall goals of this CRUK Grand Challenge project are to: 1) understand the mechanisms by which chronic inflammation (CI) promotes cancer formation and the role that the stromal microenvironment plays in this process, 2) develop an entirely new class of tissue ‘normalising’ (differentiation-inducing) therapeutics that prevent CI-associated cancer (CIAC) progression or induce existing cancers to revert to non-malignant tissue by targeting the stroma, and 3) to create novel diagnostics that can prospectively identify patients with Barrett’s Oesophagus (BO) whose lesions have a high risk of becoming cancerous. We will confront this challenge by gaining access to unique clinical samples from CIACs patients that contain morphologically-normal, metaplastic, dysplastic, and cancerous regions within the same specimen, as well as serial surveillance biopsies from BO patients. We will then leverage multiple advanced imaging, analytic, and simulation technologies, including single-cell transcriptomics, CODEX and mathematical modeling of cellular community dynamics, to create spatial maps of cellular composition and mechanical properties of the tissues during CIAC progression, as well as define intercellular and signaling circuitry. In parallel, we will engineer novel in vitro and in vivo recombinant models of CIAC progression mixing and matching cells isolated from morphologically-normal, metaplastic, dysplastic, and cancerous regions of the clinical specimens and leveraging new murine GEMs, organoid and human organ-on-a-chip (Organ Chip) microfluidic culture technologies. A novel computational discovery platform that combines systems biology, bioinformatics, machine learning, and computer-assisted drug design approaches will be used in combination with the high dimensional data sets and models of intercellular signaling circuitry described above to identify putative molecular targets as well as to develop novel stroma-modifying drugs and targeted cellular therapies that prevent CIAC progression or induce cancers to revert to non-malignant states. The efficacy of this new class of tissue normalizing therapeutics will be validated in our Organ Chip models in vitro and in human recombinant mouse models in vivo. Potential indicators of transitions from metaplasia to dysplasia and cancer that emerge from these studies will be used to develop signatures for risk stratification that can predict which patients with BO will progress to malignancy. All studies will focus initially on the mechanism of CIAC formation using oesophageal adenocarcinoma as a model system, but these studies will be extended to include CI-associated colon, gastric, and lung carcinomas, and hence the common principles, targets and signatures we discover have the potential to positively impact the care of ~25% of all cancer patients.

Lay abstract: The overall goals of this CRUK Grand Challenge project are to: 1) understand the mechanisms by which chronic inflammation (CI) promotes cancer formation and the role that the stromal microenvironment plays in this process, 2) develop an entirely new class of tissue ‘normalising’ (differentiation-inducing) therapeutics that prevent CI-associated cancer (CIAC) progression or induce existing cancers to revert to non-malignant tissue by targeting the stroma, and 3) to create novel diagnostics that can prospectively identify patients with Barrett’s Oesophagus (BO) whose lesions have a high risk of becoming cancerous. We will confront this challenge by gaining access to unique clinical samples from CIACs patients that contain morphologically-normal, metaplastic, dysplastic, and cancerous regions within the same specimen, as well as serial surveillance biopsies from BO patients. We will then leverage multiple advanced imaging, analytic, and simulation technologies, including single-cell transcriptomics, CODEX and mathematical modeling of cellular community dynamics, to create spatial maps of cellular composition and mechanical properties of the tissues during CIAC progression, as well as define intercellular and signaling circuitry. In parallel, we will engineer novel in vitro and in vivo recombinant models of CIAC progression mixing and matching cells isolated from morphologically-normal, metaplastic, dysplastic, and cancerous regions of the clinical specimens and leveraging new murine GEMs, organoid and human organ-on-a-chip (Organ Chip) microfluidic culture technologies. A novel computational discovery platform that combines systems biology, bioinformatics, machine learning, and computer-assisted drug design approaches will be used in combination with the high dimensional data sets and models of intercellular signaling circuitry described above to identify putative molecular targets as well as to develop novel stroma-modifying drugs and targeted cellular therapies that prevent CIAC progression or induce cancers to revert to non-malignant states. The efficacy of this new class of tissue normalizing therapeutics will be validated in our Organ Chip models in vitro and in human recombinant mouse models in vivo. Potential indicators of transitions from metaplasia to dysplasia and cancer that emerge from these studies will be used to develop signatures for risk stratification that can predict which patients with BO will progress to malignancy. All studies will focus initially on the mechanism of CIAC formation using oesophageal adenocarcinoma as a model system, but these studies will be extended to include CI-associated colon, gastric, and lung carcinomas, and hence the common principles, targets and signatures we discover have the potential to positively impact the care of ~25% of all cancer patients.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS