Identifying Causes of Cancer Treatment Resistance Through Spatial Transcriptomic Analysis of Tumor Microenvironment Signals

Authors:

Sudhish Swain, Martin Hemberg

Date Created:

2025-01-01

Course Title:

Professor:

Not specified

About Paper:

Drug resistance, or the ability for cancer cells to become tolerantwithin a tissue. By analyzing the cell-cell interactions of numerous towards treatment methods, is associated with over 90% of cancer- cancer tissues’ spatial transcriptomic data, we sought to uncover related deaths and is one of the leading barriers to effective the mechanisms that underlie treatment resistance by investigating cancer treatment. Recent evidence suggests that the tumor the differential gene expression of cancer cells when proximate microenvironment plays a critical role in regulating immune versus distal (close versus far) to cancer-associated fibroblasts. escape, progression, and distant metastasis of cancer. Hence, Across multiple types of cancer cells, several ligand/receptor understanding how tumors evolve to resist common treatment gene pairs were commonly differentially expressed depending on methods via the tumor microenvironment is at the forefront of distance to nearest cancer-associated fibroblast. The downstream cancer research. Advances in molecular imaging technology have pathways of these genes are currently being investigated to led to the release of spatial transcriptomic instruments like the understand how they promote tumor survival and immune evasion CosMx and Xenium profilers. These machines allow for the acrossmultipletypesofcancertodeveloptherapeuticsthatincrease simultaneous monitoring of a large number of RNA and protein the efficacy of current treatments. targets while preserving the spatial context of cells and molecules The Lasting Impacts of Typhoons on Provincial Agriculture Industries in the Philippines Luke Tan, Mike Foley, Peter Huybers Harvard College | Kirkland House | Environmental Science and Engineering | 2028 Ten years after Typhoon Yolanda struck the Philippines, the the unique aggregation method of “hybrid boundaries” to ensure nation’s agriculture industry appears to have made a speedy spatial continuity over time, we observe significant changes in recovery: the majority of the natural disaster’s recorded damage the Area Cultivated, Quantity Produced, and Calculated Yield for was humanitarian rather than agricultural, per USDA and FAO provinces in the direct line of Typhoon Pablo (2012), Typhoon reports. However, examining agricultural data at a provincial levelYolanda (2013), and Typhoon Glenda (2014). rather than at a national level reveals significant damage in specific high-valueindustries for individualprovinces. This project aimsto From this data, we find that severe weather events caused investigate the impact of Typhoon Yolanda and similar storms in significantlossesonparticularhigh-valuecropsincludingcoconut, adjacent years on the Philippine agriculture industry, with a focuscalamansi, and sugarcane. This study reinforces the importance of collecting and analyzing data at a subnational level: though the on subnational trends. national coconut industry appears to have had a speedy recovery, it Todoso, wedigitized, extracted, andaggregateddatafromsources has remained significantly below pre-typhoon levels in provinces including the USAID Famine Early Warning System (FEWS) and such as Leyte. Going forward, we begin to consider questions Philippine Statistics Authority (PSA) to build a comprehensive regarding provincial-level agricultural recovery and identifying subnational agricultural dataset for the last 40 years. Utilizing crops that are resilient to climate change-induced natural disasters. DestabilizedTetracycline-ControlledTransactivatorasaMeansforInducible Gene Expression with Rapid Turn-Off Kinetics Albert Tang, Eric Michael Moult, Adam Ezra Cohen Harvard College | Mather House | Chemistry and Physics | 2028 Drug-inducible promoters are powerful tools in engineering many irreversiblybindstothefluorescentJF585HaloTagligand, totrack biological constructs. One well-known drug-inducible promoter tTA degradation. We expressed MODC-tTA-HaloTag, ecDHFR- is tetracycline-controlled transactivator (tTA), which promotes tTA-HaloTag, and H2B-HaloTag (control with long fluorescence expression of a target gene only when tetracycline or other suitablhalf-life) in neurons, created a fluorescent “pulse” via an injection “switch” molecules are absent. However, promoters like tTA can of JF585 dye to tag existing HaloTag protein, washed out excess persist in their active states for hours after the “switch” moleculJF585 dye, and “chased” the fluorescent signal by imaging over removed, preventing rapid shut-off of tTA-dependent constructs. the course of several hours. We then compared the decay in As such, tTA and similar drug-inducible promoters cannot be used fluorescence of each destabilized tTA variant to that of the control. to build mechanisms requiring tight control over gene expression, The completion of this pulse-chase experiment will shed light onto such as those used in studying rapid neuronal firing mechanics a general methodology to improve the turn-off kinetics of any in the brain. This study fuses destabilizing domains MODC and inducible promoter-based system. Furthermore, it will develop ecDHFR to tTA as a means to degrade active tTA to improve more tools for measuring characteristics of the brain. the promoter’s turn-off kinetics. We use HaloTag protein, which

Abstract:

Drug resistance, or the ability for cancer cells to become tolerantwithin a tissue. By analyzing the cell-cell interactions of numerous towards treatment methods, is associated with over 90% of cancer- cancer tissues’ spatial transcriptomic data, we sought to uncover related deaths and is one of the leading barriers to effective the mechanisms that underlie treatment resistance by investigating cancer treatment. Recent evidence suggests that the tumor the differential gene expression of cancer cells when proximate microenvironment plays a critical role in regulating immune versus distal (close versus far) to cancer-associated fibroblasts. escape, progression, and distant metastasis of cancer. Hence, Across multiple types of cancer cells, several ligand/receptor understanding how tumors evolve to resist common treatment gene pairs were commonly differentially expressed depending on methods via the tumor microenvironment is at the forefront of distance to nearest cancer-associated fibroblast. The downstream cancer research. Advances in molecular imaging technology have pathways of these genes are currently being investigated to led to the release of spatial transcriptomic instruments like the understand how they promote tumor survival and immune evasion CosMx and Xenium profilers. These machines allow for the acrossmultipletypesofcancertodeveloptherapeuticsthatincrease simultaneous monitoring of a large number of RNA and protein the efficacy of current treatments. targets while preserving the spatial context of cells and molecules The Lasting Impacts of Typhoons on Provincial Agriculture Industries in the Philippines Luke Tan, Mike Foley, Peter Huybers Harvard College | Kirkland House | Environmental Science and Engineering | 2028 Ten years after Typhoon Yolanda struck the Philippines, the the unique aggregation method of “hybrid boundaries” to ensure nation’s agriculture industry appears to have made a speedy spatial continuity over time, we observe significant changes in recovery: the majority of the natural disaster’s recorded damage the Area Cultivated, Quantity Produced, and Calculated Yield for was humanitarian rather than agricultural, per USDA and FAO provinces in the direct line of Typhoon Pablo (2012), Typhoon reports. However, examining agricultural data at a provincial levelYolanda (2013), and Typhoon Glenda (2014). rather than at a national level reveals significant damage in specific high-valueindustries for individualprovinces. This project aimsto From this data, we find that severe weather events caused investigate the impact of Typhoon Yolanda and similar storms in significantlossesonparticularhigh-valuecropsincludingcoconut, adjacent years on the Philippine agriculture industry, with a focuscalamansi, and sugarcane. This study reinforces the importance of collecting and analyzing data at a subnational level: though the on subnational trends. national coconut industry appears to have had a speedy recovery, it Todoso, wedigitized, extracted, andaggregateddatafromsources has remained significantly below pre-typhoon levels in provinces including the USAID Famine Early Warning System (FEWS) and such as Leyte. Going forward, we begin to consider questions Philippine Statistics Authority (PSA) to build a comprehensive regarding provincial-level agricultural recovery and identifying subnational agricultural dataset for the last 40 years. Utilizing crops that are resilient to climate change-induced natural disasters. DestabilizedTetracycline-ControlledTransactivatorasaMeansforInducible Gene Expression with Rapid Turn-Off Kinetics Albert Tang, Eric Michael Moult, Adam Ezra Cohen Harvard College | Mather House | Chemistry and Physics | 2028 Drug-inducible promoters are powerful tools in engineering many irreversiblybindstothefluorescentJF585HaloTagligand, totrack biological constructs. One well-known drug-inducible promoter tTA degradation. We expressed MODC-tTA-HaloTag, ecDHFR- is tetracycline-controlled transactivator (tTA), which promotes tTA-HaloTag, and H2B-HaloTag (control with long fluorescence expression of a target gene only when tetracycline or other suitablhalf-life) in neurons, created a fluorescent “pulse” via an injection “switch” molecules are absent. However, promoters like tTA can of JF585 dye to tag existing HaloTag protein, washed out excess persist in their active states for hours after the “switch” moleculJF585 dye, and “chased” the fluorescent signal by imaging over removed, preventing rapid shut-off of tTA-dependent constructs. the course of several hours. We then compared the decay in As such, tTA and similar drug-inducible promoters cannot be used fluorescence of each destabilized tTA variant to that of the control. to build mechanisms requiring tight control over gene expression, The completion of this pulse-chase experiment will shed light onto such as those used in studying rapid neuronal firing mechanics a general methodology to improve the turn-off kinetics of any in the brain. This study fuses destabilizing domains MODC and inducible promoter-based system. Furthermore, it will develop ecDHFR to tTA as a means to degrade active tTA to improve more tools for measuring characteristics of the brain. the promoter’s turn-off kinetics. We use HaloTag protein, which

Source:

Harvard / Anthony Striker, Julia Paoli, Jessica Whited / 2025

Topics:

cancer, tta, treatment, gene, typhoon, promoter, spatial, tumor, cell, drug, expression, industry

Co-authors:

@sudhishswain374 , @martinhemberg375