# Role of the CD44/Hyaluronan axis in mesenchymal prostate cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $522,281

## Abstract

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer that
results into multiple different tumor states. Recent classifications efforts have revealed that besides the androgen
receptor pathway positive adenocarcinomas (CRPC-AD) and the terminal neuroendocrine tumors (NEPC), there
are also tumors enriched in a “hybrid state” characterized by the expression of mesenchymal and stem cell traits.
This phenotype is termed mesenchymal and stem-like prostate cancer (MSPC). The overarching goal of this
application is to identify novel molecular mechanisms underlying the MSPC phenotype that can be targeted
therapeutically. Our hypothesis is that the loss of PKCλ/ ι
(encoded by PRKCI gene), by upregulating the
CD44/Hyaluronan (HA) axis, induces the mesenchymal phenotype characterized by the activation of epithelial
EMT and the generation of desmoplastic tumor stroma, both critical events for tumor progression and therapy
resistance. We postulate that the detailed characterization of the mechanisms whereby PKCλ/ ι controls the
CD44/HA axis will provide critical new information on the molecular pathways leading to MSPC progression and
will offer a rationale for the selection of patients susceptible to respond to new therapies designed at
mesenchymal/stromal targets. Our preliminary data demonstrate that (1) human MSPC has low PRKCI levels
and a highly desmoplastic stroma; (2) PKCλ/ ι loss in the prostate epithelium in vivo induces EMT and promotes
a desmoplastic response that remodels the tumor microenvironment; (3) Low PRKCI levels correlate with
upregulation of the CD44/HA axis in human PCa, supporting the human relevance of these findings. Based on
these premises, in this proposal we will address the following specific Aims: Aim 1A: Determine how interfering
with CD44 or its ligands (OPN/SPP1, HA) block MSPC and enzalutamide resistance promoted by PKCλ/ ι-
deficiency in the epithelium; Aim 1B: Determine the role of the CD44/HA axis in stromal activation and the
stromal-epithelial feedback crosstalk; Aim 1C: Determine the molecular mechanism whereby PKCλ/ ι regulates
CD44; Aim 2A: Determine the role of prostate epithelial CD44 in driving MSPC in vivo; Aim 2B: Determine the
role of prostate stromal CD44 in driving MSPC in vivo; Aim 3A: Determine the therapeutic potential of PEGPH20
in combination with enzalutamide in the treatment of MSPC tumors and Aim 3B: Investigate its mechanism of
action at a single-cell level. The results of this proposal will contribute to a more comprehensive understanding
of the mechanisms driving the MSPC type of PCa and will be key for the design of new more selective and
effective therapies for this type of aggressive neoplasia.

## Key facts

- **NIH application ID:** 10896210
- **Project number:** 5R01CA277857-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Maria Teresa Diaz Meco Conde
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $522,281
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896210

## Citation

> US National Institutes of Health, RePORTER application 10896210, Role of the CD44/Hyaluronan axis in mesenchymal prostate cancer (5R01CA277857-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10896210. Licensed CC0.

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