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MRL proteins cooperate with activated Ras in glia to drive distinct oncogenic outcomes

E Taylor¹, N Alqadri¹, L Dodgson^1,2

¹Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.

|March 28, 2017

Abstract:

The Mig10/RIAM/Lpd (MRL) adapter protein Lpd regulates actin dynamics through interactions with Scar/WAVE and Ena/VASP proteins to promote the formation of cellular protrusions and to stimulate invasive migration. However, the ability of MRL proteins to interact with multiple actin regulators and to promote serum response factor (SRF) signalling has raised the question of whether MRL proteins employ alternative downstream mechanisms to drive oncogenic processes in a context-dependent manner. Here, using a Drosophila model, we show that overexpression of either human Lpd or its Drosophila orthologue Pico can promote growth and invasion of Ras^V12-induced cell tumours in the brain. Notably, effects were restricted to two populations of Repo-positive glial cells: an invasive population, characterized by JNK-dependent elevation of Mmp1 expression, and a hyperproliferative population lacking elevated JNK signalling. JNK activation was not triggered by reactive immune cell signalling, implicating the involvement of an intrinsic stress response. The ability to promote dissemination of Ras^V12-induced tumours was shared by a subset of actin regulators, including, most prominently, Chicadee/Profilin, which directly interacts with Pico, and, Mal, a cofactor for serum response factor that responds to changes in G:F actin dynamics. Suppression of Mal activity partially abrogated the ability of pico to promote invasion of Ras^V12 tumours. Furthermore, we found that larval glia are enriched for serum response factor expression, explaining the apparent sensitivity of glial cells to Pico/Ras^V12 overexpression. Taken together, our findings indicate that MRL proteins cooperate with oncogenic Ras to promote formation of glial tumours, and that, in this context, Mal/serum response factor activation is rate-limiting for tumour dissemination.

Insights

Mig10/RIAM/Lpd (MRL) proteins and oncogenic Ras cooperate to drive glial tumor growth and invasion in Drosophila. Mal/serum response factor (SRF) pathway activation is critical for tumor spread.

Area of Science:

Cell Biology
Developmental Biology
Cancer Biology

Background:

Mig10/RIAM/Lpd (MRL) adapter proteins regulate actin dynamics and cellular protrusions.
MRL proteins interact with Scar/WAVE and Ena/VASP proteins, influencing cell migration.
The role of MRL proteins in oncogenic processes and context-dependent signaling remains incompletely understood.

Purpose of the Study:

To investigate the role of Lpd/Pico and other actin regulators in Ras-driven tumor formation and invasion using a Drosophila model.
To elucidate the downstream signaling pathways, including JNK and Mal/SRF, involved in MRL-mediated oncogenesis.
To determine the specific glial cell populations affected by MRL overexpression and Ras activation.

Main Methods:

Overexpression of human Lpd or Drosophila Pico in a Drosophila brain tumor model (Ras^V12).
Analysis of glial cell populations (Repo-positive), JNK signaling, Mmp1 expression, and tumor invasion.
Investigated interactions with actin regulators Chicadee/Profilin and Mal, and assessed the impact of Mal suppression on tumor invasion.
Examined serum response factor (SRF) expression in larval glia.

Main Results:

Overexpression of Lpd or Pico promoted growth and invasion of Ras^V12-induced brain tumors in specific Repo-positive glial cell populations.
Tumor invasion was associated with JNK-dependent Mmp1 expression, while proliferation occurred independently of JNK signaling.
Actin regulators Chicadee/Profilin and Mal contributed to tumor dissemination, with Mal/SRF pathway activation being rate-limiting for invasion.
Larval glia showed enrichment for SRF expression, correlating with sensitivity to Pico/Ras^V12.

Conclusions:

MRL proteins cooperate with oncogenic Ras to promote glial tumor formation and invasion.
The Mal/SRF signaling pathway is a crucial mediator of tumor cell dissemination in this context.
Findings highlight context-dependent mechanisms of MRL proteins in driving oncogenesis, involving specific glial cell responses and intrinsic stress pathways.

Read full analysis

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